The ultimate goal of this project is to establish the laboratory opossum, Monodelphis domestica, as a unique model for determining the effects of diet and genotype on lipoprotein phenotypes and development of atherosclerosis. In conjunction with Project 5 and 6 Project 4 will help identify specific genes that control dietary responsiveness and ascertain their mechanisms of action. We will study a total of 350 opossums derived from different genetic stocks; high responders to saturated fat and cholesterol diet, low responders to the same diet, and two other previously uncharacterized genetic stocks. All animals will be bled while feeding the basal maintenance diet and 8, 16 and 24 weeks after feeding one of five diets differing in amounts and types of fat and in cholesterol levels. The first specific aim is to determine lipoprotein phenotypes in plasma samples taken from each animal while consuming the basal diet, and periodically during 24 weeks while consuming one of the challenge diets. Lipoprotein phenotypes will be total cholesterol determined using nondenaturing gradient gel electrophoresis. The results will enable us to determine whether, for some stocks but not others, significant changes in lipoprotein phenotypes are attributable to increases in either of two types of fat (polyunsaturated and saturated) or in cholesterol. The second specific aim is to measure extent and severity of atherosclerotic lesions in all animals and to determine their relationship with time-weighted or aggregate lipoprotein phenotypes. Animals will necropsied after the last (24 week) blood sampling in order to quantify atherosclerotic lesions. The results will enable us to determine whether aspects of lipoprotein phenotypes (including cholesterol levels and particle sizes for the two major types of lipoprotein, very low density plus low density lipoprotein and high density lipoprotein) are associated with extent and severity of lesions. Previous results indicating genetic control of responder phenotype and of high density lipoprotein levels suggest the exciting potential of the opossum model in determining genetic and environmental factors relevant to cardiovascular disease.